Drug targets for Cancer: Bcr-Abl

Drug Targets for Cancer: Bcr-Abl and Cancer

The BCR-ABL is one of the nonreceptor tyrosine kinases, It transduces diverse extracellular signals to protein networks that control proliferation, survival, migration, and invasion. ABL1 was first identified as an oncogene required for the development of leukemias initiated by retroviruses or chromosome translocations. The demonstration that small molecule Bcr-Abl kinase inhibitors effectively treat chronic myeloid leukemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for Bcr-Abl in solid tumors. Enhanced ABL expression and activation in some solid tumors, together with altered cell polarity, invasion or growth induced by activated Bcr-Abl, suggest that drugs targeting these kinases may have utility in treating selected solid tumors. Oncogenic activation of the ABL kinases occurs in Philadelphia-positive (Ph+) human leukemias as a consequence of the t(9;22)(q34;q11) chromosome translocation that generates BCR-ABL1 fusion proteins with constitutive tyrosine kinase activity. Three different BCR-ABL1 proteins have been identified that differ in the amount of BCR sequences retained in the fusion protein, and which are associated with distinct types of leukemia: P210 BCR-ABL1 is the molecular hallmark of CML; P185 BCRABL1 is present in 20-30% of adult and 3-5% of childhood B-cell acute lymphocytic leukemia (B-ALL)44, 45; and P230 BCR-ABL1 has been detected in neutrophilic-CML46 as well as rare cases of CML. Accumulating data support a role for ABL kinases in solid tumors characterized by enhanced expression and/or activation of these kinases. The Cancer Genome Atlas (TCGA) and other studies have shown that ABL1 are amplified and/or overexpressed in invasive breast carcinoma, ovarian serous cystadenocarcinoma, lung adenocarcinoma, and lung squamous cell carcinoma. Alterations in ABL1 are also found in skin cutaneous melanoma, bladder urothelial carcinoma, colorectal adenocarcinoma, rhabdoid tumors, as well as renal medullary and clear cell renal carcinoma

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Drug Targets for Cancer: Bcr-Abl Related Reference

Greuber E K, Smith-Pearson P, Wang J, et al. Role of ABL family kinases in cancer: from leukaemia to solid tumours[J]. Nature Reviews Cancer, 2013, 13(8): 559-571.

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